Posted on by Dr. Francis Collins
More than 30 years ago, I co-led the Michigan-Toronto team that discovered that cystic fibrosis (CF) is caused by an inherited misspelling in the cystic fibrosis transmembrane conductance regulator (CFTR) gene . The CFTR protein’s normal function on the surface of epithelial cells is to serve as a gated channel for chloride ions to pass in and out of the cell. But this function is lost in individuals for whom both copies of CFTR are misspelled. As a consequence, water and salt get out of balance, leading to the production of the thick mucus that leaves people with CF prone to life-threatening lung infections.
It took three decades, but that CFTR gene discovery has now led to the development of a precise triple drug therapy that activates the dysfunctional CFTR protein and provides major benefit to most children and adults with CF. But about 10 percent of individuals with CF have mutations that result in the production of virtually no CFTR protein, which means there is nothing for current triple therapy to correct or activate.
That’s why more basic research is needed to tease out other factors that contribute to CF and, if treatable, could help even more people control the condition and live longer lives with less chronic illness. A recent NIH-supported study, published in the journal Nature Medicine , offers an interesting basic clue, and it’s visible in the image above.
The healthy lung tissue (left) shows a well-defined and orderly layer of ciliated cells (green), which use hair-like extensions to clear away mucus and debris. Running closely alongside it is a layer of basal cells (outlined in red), which includes stem cells that are essential for repairing and regenerating upper airway tissue. (DNA indicating the position of cell is stained in blue).
In the CF-affected airways (right), those same cell types are present. However, compared to the healthy lung tissue, they appear to be in a state of disarray. Upon closer inspection, there’s something else that’s unusual if you look carefully: large numbers of a third, transitional cell subtype (outlined in red with green in the nucleus) that combines properties of both basal stem cells and ciliated cells, which is suggestive of cells in transition. The image below more clearly shows these cells (yellow arrows).
The increased number of cells with transitional characteristics suggests an unsuccessful attempt by the lungs to produce more cells capable of clearing the mucus buildup that occurs in airways of people with CF. The data offer an important foundation and reference for continued study.
These findings come from a team led by Kathrin Plath and Brigitte Gomperts, University of California, Los Angeles; John Mahoney, Cystic Fibrosis Foundation, Lexington, MA; and Barry Stripp, Cedars-Sinai, Los Angeles. Together with their lab members, they’re part of a larger research team assembled through the Cystic Fibrosis Foundation’s Epithelial Stem Cell Consortium, which seeks to learn how the disease changes the lung’s cellular makeup and use that new knowledge to make treatment advances.
In this study, researchers analyzed the lungs of 19 people with CF and another 19 individuals with no evidence of lung disease. Those with CF had donated their lungs for research in the process of receiving a lung transplant. Those with healthy lungs were organ donors who died of other causes.
The researchers analyzed, one by one, many thousands of cells from the airway and classified them into subtypes based on their distinctive RNA patterns. Those patterns indicate which genes are switched on or off in each cell, as well as the degree to which they are activated. Using a sophisticated computer-based approach to sift through and compare data, the team created a comprehensive catalog of cell types and subtypes present in healthy airways and in those affected by CF.
The new catalogs also revealed that the airways of people with CF had alterations in the types and proportions of basal cells. Those differences included a relative overabundance of cells that appeared to be transitioning from basal stem cells into the specialized ciliated cells, which are so essential for clearing mucus from the lungs.
We are not yet at our journey’s end when it comes to realizing the full dream of defeating CF. For the 10 percent of CF patients who don’t benefit from the triple-drug therapy, the continuing work to find other treatment strategies should be encouraging news. Keep daring to dream of breathing free. Through continued research, we can make the story of CF into history!
 Identification of the cystic fibrosis gene: chromosome walking and jumping. Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole JL, Kennedy D, Hidaka N, et al. Science.1989 Sep 8;245(4922):1059-65.
 Transcriptional analysis of cystic fibrosis airways at single-cell resolution reveals altered epithelial cell states and composition. Carraro G, Langerman J, Sabri S, Lorenzana Z, Purkayastha A, Zhang G, Konda B, Aros CJ, Calvert BA, Szymaniak A, Wilson E, Mulligan M, Bhatt P, Lu J, Vijayaraj P, Yao C, Shia DW, Lund AJ, Israely E, Rickabaugh TM, Ernst J, Mense M, Randell SH, Vladar EK, Ryan AL, Plath K, Mahoney JE, Stripp BR, Gomperts BN. Nat Med. 2021 May;27(5):806-814.
Cystic Fibrosis (National Heart, Lung, and Blood Institute/NIH)
Kathrin Plath (University of California, Los Angeles)
Brigitte Gomperts (UCLA)
Stripp Lab (Cedars-Sinai, Los Angeles)
Cystic Fibrosis Foundation (Lexington, MA)
Epithelial Stem Cell Consortium (Cystic Fibrosis Foundation, Lexington, MA)
NIH Support: National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of General Medical Sciences; National Cancer Institute; National Center for Advancing Translational Sciences
Posted on by Dr. Francis Collins
The image above shows a small section of the trachea, or windpipe, of a developing mouse. Although it’s only about the diameter of a pinhead at this stage of development, the mouse trachea has a lot in common structurally with the much wider and longer human trachea. Both develop from a precisely engineered balance between the flexibility of smooth muscle and the supportive strength and durability of cartilage.
Here you can catch a glimpse of this balance. C-rings of cartilage (red) wrap around the back of the trachea, providing the support needed to keep its tube open during breathing. Attached to the ends of the rings are dark shadowy bands of smooth muscles, which are connected to a web of nerves (green). The tension supplied by the muscle cells is essential for proper development of those neatly organized cartilage rings.